Olfactory receptors belong to the superfamily of seven transmembrane domain (7TD), G protein-coupled receptors (GPCRs). In other well-studied members of this superfamily, molecular modeling techniques have provided insights into the structure of these receptors as well as the mechanisms of their interactions with neurotransmitter ligands. We have employed similar techniques to construct a three- dimensional model of the OR5 olfactory receptor, which has been expressed in the baculovirus system and has been shown to bind preferentially to lyral (Raming et al., 1993). Models were built with conventional software, and interactions between the receptor and the lyral ligand were analyzed to locate potential ligand binding residues.
A group of potential ligand binding residues of the OR5 receptor formed a putative binding pocket approximately 12 from the extracellular surface of the receptor. This pocket is similar to that found thus far for all other members of the superfamily. The most important of the residues were Tyr 278, which formed a hydrogen bond with the aldehyde carbonyl of lyral; Leu 245, which formed van der Waals interactions with the cyclohexenyl ring; and Phe 104, which formed similar interactions with the ring. Leu 245 corresponds in position to a conserved aromatic residue in helix VI of other GPCRs (e.g. beta- adrenergic receptor: bAR) that is implicated in hydrophobic shielding of charged groups (bAR 289). Moreover, Phe 104 corresponds to the aspartate conserved in helix III of aminergic and cholinergic receptors (bAR 113), which acts as a counterion to the cationic amine of the ligand. Phe 104 and Leu 245 also correspond to residues that stabilize retinal in the bacteriorhodopsin photoreceptor. Other potential ligand binding residues were located in helices III through VI; many of these also correspond to ligand binding residues conserved in other superfamily members.
On the basis of these results, we hypothesize that odor reception occurs in a binding pocket similar that of other GPCRs. Within this pocket, specific residues appear to interact with specific functional groups of an odor ligand known to activate this receptor. The results thus provide insight into possible molecular mechanisms of odor detection and discrimination, and suggest strategies that can be used in future experimental analysis employing site-directed mutagenesis.
Supported by a grant from NIDCD to GMS.